ArticleAntimicrobial agents and chemotherapy2014
Identification of a key lysine residue in heat shock protein 90 required for azole and echinocandin resistance in Aspergillus fumigatus.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 70 citations in OpenAlex.
- Antifungal resistance: from classical mechanisms to the expanding role of acetyltransferases.Journal of biomedical science · 2026Review
- Genotype-Phenotype Relationships in Azole-ResistantJournal of fungi (Basel, Switzerland) · 2026Review
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- Antifungal susceptibility and genomic profile associated with biosynthetic gene clusters of bovine mastitis-derivedFrontiers in microbiology · 2026Article
- Post-transcriptional control of antifungal resistance in human fungal pathogens.Critical reviews in microbiology · 2023Review
- Molecular mechanisms governing antifungal drug resistance.npj antimicrobials and resistance · 2023Review
- Potential Antifungal Targets forInternational journal of molecular sciences · 2022Review
- Epigenetic Regulation of Antifungal Drug Resistance.Journal of fungi (Basel, Switzerland) · 2022Review
- Potential antifungal targets based on histones post-translational modifications against invasive aspergillosis.Frontiers in microbiology · 2022Review
- Therapeutic Approaches for CombatingCurrent drug targets · 2022Review
- Fungal Lysine Deacetylases in Virulence, Resistance, and Production of Small Bioactive Compounds.Genes · 2021Review
- Aspergillus fumigatus Hsp90 interacts with the main components of the cell wall integrity pathway and cooperates in heat shock and cell wall stress adaptation.Cellular microbiology · 2021Article
- Identification and Phenotypic Characterization of Hsp90 Phosphorylation Sites That Modulate Virulence Traits in the Major Human Fungal PathogenFrontiers in cellular and infection microbiology · 2021Article
- Pathogen-Host Interaction Repertoire at Proteome and Posttranslational Modification Levels During Fungal Infections.Frontiers in cellular and infection microbiology · 2021Review
- Marine Bioactive Compounds againstAntibiotics (Basel, Switzerland) · 2020Review
- Novel Antifungal Agents and Their Activity againstJournal of fungi (Basel, Switzerland) · 2020Review
- Post-translational modifications of Hsp90 and translating the chaperone code.The Journal of biological chemistry · 2020Review
- Lysine acetylation as drug target in fungi: an underexplored potential in Aspergillus spp.Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology] · 2020Review
- Synergistic effects of vorinostat (SAHA) and azoles against Aspergillus species and their biofilms.BMC microbiology · 2020Article
- Protein Acetylation/Deacetylation: A Potential Strategy for Fungal Infection Control.Frontiers in microbiology · 2020Review
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Heat shock protein 90 (Hsp90) is an essential chaperone involved in the fungal stress response that can be harnessed as a novel antifungal target for the treatment of invasive aspergillosis. We previously showed that genetic repression of Hsp90 reduced Aspergillus fumigatus virulence and potentiated the effect of the echinocandin caspofungin. In this study, we sought to identify sites of posttranslational modifications (phosphorylation or acetylation) that are important for Hsp90 function in A. fumigatus. Phosphopeptide enrichment and tandem mass spectrometry revealed phosphorylation of three residues in Hsp90 (S49, S288, and T681), but their mutation did not compromise Hsp90 function. Acetylation of lysine residues of Hsp90 was recovered after treatment with deacetylase inhibitors, and acetylation-mimetic mutations (K27A and K271A) resulted in reduced virulence in a murine model of invasive aspergillosis, supporting their role in Hsp90 function. A single deletion of lysine K27 or an acetylation-mimetic mutation (K27A) resulted in increased susceptibility to voriconazole and caspofungin. This effect was attenuated following a deacetylation-mimetic mutation (K27R), suggesting that this site is crucial and should be deacetylated for proper Hsp90 function in antifungal resistance pathways. In contrast to previous reports in Candida albicans, the lysine deacetylase inhibitor trichostatin A (TSA) was active alone against A. fumigatus and potentiated the effect of caspofungin against both the wild type and an echinocandin-resistant strain. Our results indicate that the Hsp90 K27 residue is required for azole and echinocandin resistance in A. fumigatus and that deacetylase inhibition may represent an adjunctive anti-Aspergillus strategy.
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